Induction with levomethadyl acetate: safety and efficacy.

BACKGROUND: Levomethadyl acetate hydrochloride (known as LAAM) is a mu-opioid agonist approved for the treatment of opioid dependence. Clinical trials comparing LAAM and methadone have reported lower patient retention rates during LAAM induction; however, this may reflect dose and schedule differences. Few studies have systematically examined LAAM dose induction. This study compared induction with 3 different LAAM dosage levels. METHODS: In a randomized, double-blind trial, male and female opioid-dependent patients (N = 180) were assigned to 1 of 3 LAAM doses. The low-dose (25 mg) induction was constant from the onset of treatment, the medium-dose (50 mg) induction lasted 7 days, and the high-dose (100 mg) induction lasted 17 days. Safety and efficacy were assessed on retention, urinalysis and self-reported drug use, symptoms, and patient ratings of medication adequacy. RESULTS: The high-dose group had significantly fewer illicit opioid-positive urine samples in weeks 3 and 4 as compared with the low-dose group. The high-dose group had significantly lower self-reported heroin craving in weeks 2 and 3. All groups demonstrated significant decreases in illicit drug use, withdrawal symptoms, and depression. There were no between-group differences in retention; however, there was a trend (P = .08) for lower retention and a greater number of agonist adverse effects were observed in the high-dose group. Overall, LAAM doses were well tolerated by most patients. CONCLUSION: Induction with low and medium LAAM doses can be safely and effectively achieved within 7 days. Induction with higher LAAM doses can be safely achieved within 17 days, but may result in greater rates of patient dropout and opioid agonist adverse effects. Therefore, higher doses should be approached more slowly.

Effects of smoke deprivation interval on puff topography.

Our purpose in this series of three studies was to determine the effects of deprivation interval on smoking topography. In experiment 1, subjects were allowed to smoke ad libitum for 1 hour after 3, 30, and 300 minutes of tobacco smoke deprivation. An increased latency to the first cigarette developed after 3 minutes deprivation and an increase in the number of cigarettes smoked occurred after 300 minutes of deprivation. In experiment 2, puff number and spacing were held constant to determine if smokers would compensate for long deprivation intervals by more intense smoking, i.e., increased puff volume. Puff volumes and carbon monoxide (CO) boosts did not differ across smoking bouts preceded by either 30, 100, or 300 minutes of tobacco smoke deprivation. In experiment 3, average puff volumes and CO boosts were examined during smoking periods with short (3, 10, and 30 minutes) deprivation intervals. Subjects smoked less intensely (lower puff volumes and CO boosts) when smoking was spaced by 3 than by 30 minutes. We conclude that smokers do not increase puff volume after long deprivation intervals up to 300 minutes, but they may decrease puff volumes after short (3 minutes) deprivation intervals when puff number and spacing cannot be used as compensatory mechanisms.

Acute physical dependence: time course and relation to human plasma morphine concentrations.

OBJECTIVES: To characterize the postmorphine time course of precipitated withdrawal responses in comparison with the time course of opioid agonist effects and of plasma morphine concentrations. BACKGROUND: The study provides a more detailed and comprehensive assessment of the postagonist time course of acute dependence effects in humans than previously available. DESIGN: Opioid agonist effects, morphine plasma levels, and withdrawal effects precipitated by naloxone (10 mg/70 kg, administered intramuscularly) were examined at 1, 3, 6, 12, 18, 24, 30, 36, and 42 hours after a single dose of morphine (18 mg/70 kg, administered intramuscularly) in 10 nondependent opioid-experienced subjects. RESULTS: The intensity of subjectively reported precipitated withdrawal effects was greatest when testing was conducted at 6 hours after morphine administration, whereas peak intensity of agonist effects (pupil constriction and subjective ratings) and highest plasma morphine concentrations (57.3 ng/ml) were observed at the shortest test interval (1 hour) after morphine. Offset time course of naloxone-precipitated effects differed across specific measures, with hot and cold feelings elevated for the longest time after morphine (36 hrs), but significant effects were generally apparent for up to 24 hours after morphine pretreatment. Agonist effects lasted through only 12 hours; trace amounts of morphine were detected in plasma for up to 30 hours after administration. CONCLUSIONS: Results show that acute physical dependence engendered by a single dose of morphine peaks later and persists over a longer duration after morphine administration than do other agonist effects. This suggests that neuronal adaptations underlying physical dependence develop and decay gradually over time during a single episode of receptor occupancy. The presence of detectable morphine in plasma is consistent with a competitive displacement mechanism of precipitated effects, although noncompetitive actions of morphine or its metabolites are not ruled out.

Single-day methadone dose alteration: detectability and symptoms.

Three experiments were conducted in which detectability and symptomatic effects of acute (single-day) increases and decreases in the methadone dose of subjects on methadone maintenance were examined. Altered doses ranged from 0% to 200% of the stable methadone dose, which was typically 50 mg. In an initial experiment, explicit information was provided to subjects (N = 10) about the occurrence and size of altered doses. No explicit information was provided in a second experiment, but subjects (N = 14) could detect altered doses on the basis of taste. In the third experiment, subjects (N = 2) received no information about the direction, size, or schedule of altered doses. Large dose alterations (75% to 100% of stable dose) were reliably detected by subjects on methadone maintenance, although marked individual differences in sensitivity were apparent. With taste cues available, subjects underestimated the magnitude of dose decreases and increases by 50% and 75%. Without taste cues, subjects could reliably detect only decreased doses. Symptomatic effects related to direction and size of altered doses but not to information conditions. Withdrawal symptom checklist scores were elevated after large (75% to 100%) dose decreases under all information conditions, but few symptomatic effects were reported after dose increases under any information condition.

Short-term effects of oral methadone in methadone maintenance subjects.

In two experiments the physiologic and subjective status of methadone maintenance patients was assessed during the presumed peak (0 to 6 hr postmethadone) and during the presumed nadir of the daily methadone effect (18 to 30 hr postmethadone). In the first experiment physiologic and subjective responses were measured in seven ambulatory subjects at 2, 4, and 6 hr after a regular daily dose of methadone or placebo. In the second, physiologic measures were continuously monitored for 4 hr in six inactive seated subjects. In both studies, pupil diameter decreased after moderate to high methadone doses (35 to 80 mg). In the second experiment, heart rate fell and skin temperature rose significantly after methadone. Responses to the morphine-benzedrine group scale of the Addiction Research Center Inventory were elevated after methadone for most subjects in both studies, although there were individual differences in the magnitude and time course of this effect. Finally, low methadone maintenance doses of 10 and 20 mg/day had little or no effect on physiologic or subjective responses in two subjects. These studies showed that short-term effects of oral methadone can be readily detected during a 24-hr dosing regimen. The changes in function after the regular maintenance dose may result both from short-term opiate effects and relief of mild withdrawal.

Pupillary response to methadone challenge in heroin users.

The relationship between self-reported illicit heroin use and pupillary response to a low-dose methadone challenge was examined in 28 men beginning methadone therapy for opiate dependence. Pupil diameter was assessed before and 60, 90, and 120 minutes after a 20 mg methadone dose on day 1 of treatment. Self-reports of opiate drug effects were also taken at these times. There was a significant negative correlation (r = -0.53) between pupillary constriction 120 minutes after drug dosing and the average dollar value of subjects' reported heroin use per week. In other words, those who showed the least pupillary constriction generally reported the highest amount of illicit heroin use. Total years since first opiate use was also a significant predictor of pupillary response (r = -0.46). Self-reported amount of heroin use and years since first opiate use together accounted for 60% of the total variance in pupillary response to the challenge (Mult r = 0.77). Pupillary response to a low-dose methadone challenge appears to be a clinically practical and objective method for determining opiate tolerance levels in applicants for methadone therapy.

Clinical pharmacology of buprenorphine: ceiling effects at high doses.

OBJECTIVE: The purpose of this study was to characterize the acute effects of buprenorphine, an opioid partial mu-agonist, across a wide range of doses in comparison to methadone. METHOD: Healthy adult male volunteers, who had experience with but were not physically dependent on opioids, participated while residing on a closed research unit. Four subjects received buprenorphine (0, 1, 2, 4, 8, 16, and 32 mg sublingually and five subjects received methadone (0, 15, 30, 45, and 60 mg orally) in ascending order at 1-week intervals. Physiologic, subjective, and behavioral measures were monitored for 96 hours after drug administration. RESULTS: Both drugs produced typical opioid agonist effects (positive mood, sedation, respiratory depression, and miosis), some of which persisted for 24 to 48 hours. A plateau was observed for the dose effects of buprenorphine on subjective measures and respiratory depression. Pharmacokinetic data revealed that plasma concentrations of buprenorphine were linearly related to dose, indicating no limits on sublingual absorption in this dose range. CONCLUSIONS: This study shows a plateau on buprenorphine effects, consistent with its partial agonist classification, and that single doses of buprenorphine up to 70 times the recommended analgesic dose are well tolerated by nondependent humans.

Oral methadone self-administration: effects of dose and alternative reinforcers.

We examined the efficacy of oral methadone as a reinforcer by offering methadone maintenance patients the chance to self-administer extra doses of methadone occasionally in addition to their regular dose. Seven maintenance patients received twice-weekly choices between methadone doses or money. Doses were 0, 1, 5, 10, 25, or 50 mg methadone; the alternative money option was $1 or $5. Extra methadone doses were reliably self-administered by maintenance patients, and percent of dose choices rose as the size of the dose offered increased. Thus extra methadone doses functioned as reinforcers in this situation. Further, across the entire dose range, more dose choices were selected when $1 was offered than when $5 was offered as an alternative. Thus methadone self-administration was influenced by the alternative reinforcers available for drug refusal. Neither reports of subjective withdrawal symptoms nor reduction of symptoms after extra methadone predicted methadone self-administration, but dose selections were more likely when urinalysis results indicated recent illicit opiate use. The reinforcing effects of oral methadone in methadone-tolerant patients may be an important factor in the popularity of this treatment among drug abusers and in the long-term treatment retention generally observed during methadone maintenance.

Diazepam and methadone interactions in methadone maintenance.

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.

A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts.

The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty-five patients were randomized to receive either sublingual buprenorphine or oral methadone under double-dummy and double-blind conditions to study the pharmacology of buprenorphine in a 90-day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between-group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self-report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts.

Comparison of buprenorphine and methadone in the treatment of opioid dependence.

OBJECTIVE: This study compared the efficacy of buprenorphine and methadone in the treatment of opioid dependence. METHOD: Participants (N = 164) were relatively treatment-naive, opioid-dependent applicants to a 26-week treatment program who were randomly assigned to either methadone or buprenorphine treatment. Dosing was double-blind and double-dummy. Patients were stabilized on a regimen of either methadone, 50 mg, or buprenorphine, 8 mg, with dose changes possible through week 16 of treatment. Urine samples were collected three times a week, and weekly counseling was provided. RESULTS: Buprenorphine (mean dose = 8.9 mg/day) and methadone (mean dose = 54 mg/day) were equally effective in sustaining retention in treatment, compliance with medication, and counseling regimens. In both groups, 56% of patients remained in treatment through the 16-week flexible dosing period. Overall opioid-positive urine sample rates were 55% and 47% for buprenorphine and methadone groups, respectively; cocaine-positive urine sample rates were 70% and 58%. Evidence was obtained for the effectiveness of dose increases in suppressing opioid, but not cocaine, use among those who received dose increases. CONCLUSIONS: The results of this study provide further support for the utility of buprenorphine as a new medication in the treatment of opioid dependence and demonstrate efficacy equivalent to that of methadone when used during a clinically guided flexible dosing procedure.

Effects of alcohol on speaking in isolated humans.

Drugs of abuse often increase human social interaction, as is suggested in our cultural drug use practices and has been demonstrated in controlled laboratory studies. The environmental and pharmacological mechanisms controlling these effects remain unclear. The present study examined the importance of a social context for obtaining drug-produced increases in human speech by examining the acute effects of alcohol (0, 22, 45, 67 g) on the amount of speech emitted by six normal volunteers who were producing speech monologues in an isolated context. A within-subject repeated-measures experimental design was used. Alcohol produced a significant dose-dependent increase in total speech. Conversely, response rates on a nonverbal behavioral task (circular-lights device) decreased as an orderly function of alcohol dose. These results suggest that a social context is not a necessary condition for alcohol to increase rates of human speech. Moreover, the decreases in response rates observed in the nonverbal task rule out the possibility that alcohol affected total speech via a generalized increase in overall activity levels.

Acute marijuana effects on social conversation.

The present study assessed the acute effects of smoked marijuana on social conversation. Speech quantity was recorded continuously in seven moderate marijuana users during separate 1 h experimental sessions following the paced smoking of 0, 1.01, 1.84, and 2.84% THC marijuana cigarettes. Subjects engaged in conversation with undrugged partners who smoked placebo marijuana cigarettes. The active marijuana produced significant decreases in speech quantity, increases in heart rate, and increases in self-reports of "high" and sedation. Partners showed no effects in speech quantity or self-reports of drug effects that were systematically related to the doses administered to the subject pair members. The effects on speech quantity observed in the present study after acute dosing are similar to the effects on social conversation reported previously during chronic marijuana dosing. Marijuana appears to be an exception to the general rule that drugs of abuse increase verbal interaction.

Opioid physical dependence development in humans: effect of time between agonist pretreatments.

We examined the effect of morphine pretreatment spacing on intensity of subsequent precipitated withdrawal response to test the hypothesis that withdrawal intensity would be inversely related to pretreatment spacing. Subjects were ten nondependent male volunteers who reported using opioids an average of 2.5 times per week. Three IM morphine injections (each 18 mg/70 kg) were administered during each of four experimental conditions. The experimental conditions involved spacing injections at 12-, 24-, 48- or 72-h intervals. Naloxone (10 mg/70 kg IM) was administered 24 h after the last morphine exposure. A comparison condition was included in which a naloxone challenge was given at 24 h following a single IM morphine pretreatment (18 mg/70 kg). Subject rated measures of symptoms and observer-rated measures of signs indicated that withdrawal intensity was inversely related to the morphine spacing interval and in particular that intensity of withdrawal precipitated after three pretreatments spaced at 12-h intervals was greater than that precipitated after a single morphine pretreatment. Physiological data supported a more intense withdrawal response in the 12-h spacing condition and provided evidence of overshoot on blood pressure and skin temperature measures. These findings are pertinent to the transition between acute and chronic physical dependence; they suggest that there is a temporal window during which repeated opioid administrations result in escalation of physical dependence but that dependence levels after widely spaced multiple exposures may be no greater than after a single exposure.

Nicotine replacement: ten-week effects on tobacco withdrawal symptoms.

This study examined the long-term effects of nicotine replacement on tobacco withdrawal symptoms. Smokers (N = 40 community volunteers) maintained biologically validated smoking abstinence under closely monitored conditions while chewing 2 mg nicotine gum (Nicorette; average of 6.9 pieces per day) or placebo gum during the first 10 weeks following smoking cessation. During the first postcessation week symptoms of irritability, anxiety, impatience, restlessness, excessive hunger, difficulty concentrating, drowsiness, sleep disturbance and tobacco craving intensity were significantly lower in active as compared with placebo nicotine gum subjects. Symptoms of psychological distress including irritability, anxiety and impatience declined over time in placebo subjects and were suppressed by replacement therapy below placebo treatment levels only during the first 4-5 weeks after smoking cessation. On other items, most notably increased appetite and excessive eating, stable between-group differences persisted over the entire 10-week trial. The data suggest that use of active gum beyond the first 5 weeks post-cessation may be inconsequential as far as suppression of certain key symptoms of psychological disturbance is concerned, but more prolonged use of active gum would be advisable if the long-term nicotine replacement effects observed (e.g. decreased hunger) are relevant to smoking relapse prevention.

Effect of d-amphetamine, secobarbital, and marijuana on choice behavior: social versus nonsocial options.

The effects of oral d-amphetamine and secobarbital and smoked marijuana on human social conversation and preference for socializing were studied in three separate experiments. During experimental sessions, active drug or placebo was administered using an acute or divided dosing procedure. Subjects who received drug then engaged in a discrete-trial choice procedure in which they made a series of mutually exclusive choices between a social (talking with their nondrugged partner) and nonsocial (sitting quietly alone) option. Lapel microphones and voice operated relays measured seconds of speech. Subjects engaged in greater amounts of conversation and chose the social option more frequently following acute dosing of d-amphetamine and secobarbital compared with placebo. Acute administration of marijuana did not significantly affect social speech or choice behavior, producing slight decreases in both measures. Acute dosing of all drugs significantly increased subjective drug effect or drug high; however, only secobarbital affected the circular lights task, producing significant performance decrements. The shifts in preference toward the social option observed with d-amphetamine and secobarbital suggest that these drugs increased the reinforcing effects of socializing relative to sitting alone. This may be one mechanism by which psychoactive drugs facilitate social conversation.

Effects of smoking cessation on caloric intake and weight gain in an inpatient unit.

The present research was designed to assess the amount of weight gain that would occur when male smokers in an inpatient setting were deprived of cigarettes for 10 days, and to evaluate factors that could contribute to that weight gain, such as caloric intake and activity level. Subjects were 17 healthy male smokers who either smoked ad libitum (n = 8) or quit smoking (n = 9) for 10 days after a 3 day smoking baseline. Caloric intake, activity levels, and body weight were assessed daily. Abstainers gained more weight than did smokers and ate more over time. There were no group differences in activity level. An analysis of energy needs versus actual energy intake suggests that caloric intake accounted for a large percentage of the post-cessation weight gain. However, considerable individual variability exists in caloric intake after smoking cessation. In addition, the study found post-cessation increases in caloric intake that were quite similar to those found in studies with females, suggesting that gender may have little to do with overall post-cessation caloric intake. Further research assessing dietary and metabolic changes after smoking cessation in a larger sample of both males and females is needed so that the reasons for and implications of dietary variability can be evaluated.

Desire to smoke during spaced smoking intervals.

This study examined the detailed time course of desire to smoke self-reports during brief periods of tobacco smoking deprivation to determine how these reports are related to amount and spacing of scheduled smoking. During four independent sessions, subjects (n = 10) smoked cigarettes at 30-, 60-, or 120-min intervals, or only smoked a single cigarette at the end of the 6-h session. At 15-min intervals, subjects answered four analog scale questions measuring their desire to smoke which were averaged to produce a single score. Mean desire to smoke scores were 28, 43, 59 and 71 in the 30-, 60-, 120- and 360-min cigarette spacing conditions, respectively, indicating an orderly relationship with amount of scheduled smoking. Patterns of change were similar across repeated observations and during several different deprivation intervals. Desire to smoke ratings, although temporarily suppressed by smoking, began rising within minutes of smoking and increased to near maximum levels (about 80 on a 100-point scale) after fewer than 3 h of abstinence. The observed rapid escalation in desire to smoke ratings during brief periods of abstinence is consistent with cigarette craving being reported by regular smokers who are not trying to quit. Further, if cravings can be accepted as a feature of tobacco withdrawal, the results support the view that avoidance of withdrawal is an important factor that maintains regular cigarette smoking.

Manipulation of cigarette craving through rapid smoking: efficacy and effects on smoking behavior.

Craving is thought to play an important role in maintaining regular smoking patterns in current smokers, and in leading to relapse in smokers attempting to quit. Within the scientific community however, the concept is surrounded by controversy. In an effort to 1) identify interventions that can reliably influence cigarette cravings, and 2) assess the relationship between cigarette craving and smoking behavior, effects of aversive rapid smoking (up to nine cigarettes with puffs taken every 6 s) on self-reported craving and subsequent smoking behavior were compared to effects of self-paced smoking or no smoking. Subjects (n = 14) engaged in a rapid, self-paced or no smoking procedure at the start of three separate sessions. Craving levels, measured repeatedly during the next 3 h of no smoking, were significantly lower after rapid smoking than after either self-paced or no smoking. Measures of subsequent smoking behavior (latency to first cigarette, number of cigarettes, number of puffs) did not differ systematically across conditions. Thus, craving was reliably suppressed by aversive rapid smoking, but craving scores did not predict actual smoking behavior.

Mecamylamine does not precipitate withdrawal in cigarette smokers.

Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept mecamylamine if it precipitates withdrawal, as it does in nicotine dependent rats. This study examined mecamylamine's effects using procedures designed to measure precipitated withdrawal symptoms in humans. Ten cigarette smokers (mean of 37.5 cigarettes/day) and ten non tobacco-using subjects participated in three 6-h sessions. After a 2-h baseline period in which smokers smoked one cigarette every 30 min, oral mecamylamine (0, 10, or 20 mg randomly ordered across sessions) was administered (double-blind). No smoking was allowed for the remainder of the session. Mecamylamine reduced blood pressure and increased heart rate relative to placebo in both the smokers and the non-tobacco users. No reliable direct subjective effects of mecamylamine were observed. Smokers' subjective reports of cigarette craving and tobacco withdrawal increased, and DSST performance was disrupted over the last 4 h of each session. Effects were independent of dose (placebo versus active). These results suggest that up to 20 mg mecamylamine will not precipitate nicotine withdrawal and that this medication would be acceptable for use in smoking cessation.